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YR5 Haematology > Multiple Myeloma and Related Plasma Cell Disorders > Flashcards

Multiple Myeloma and Related Plasma Cell Disorders Flashcards

1
Q

Define multiple myeloma.

A

Malignancy of BM plasma cells, the terminally differentiated + immunoglobulin (Ig) secreting B cells.

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2
Q

List 4 actions of myeloma plasma cells.

A

Home + infiltrate BM

May form bone expansile or soft tissue tumours: Plasmacytomas

Produce a serum monoclonal IgG or IgA: Paraprotein or M-spike

Produce excess of monoclonal (κ or λ) serum free light chains
Bence-Jones protein: Urine monoclonal free light chains

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3
Q

7 epidemiological facts of multiple myeloma.

A

2nd most common haematological malignancy, 19th in all cancers.

Median age 67y.

Incidence increases with age.

1% <40y

M > F

Black > Caucasian + Asians.

Prevalence of myeloma increasing

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4
Q

Explain the aetiology/ risk factors of multiple myeloma.

A

Aetiology is unknown.

Risk factors:

Obesity

Age

Genetics: Incidence in black population + sporadic cases of familiar myeloma

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5
Q

What is multiple myeloma always preceeded by?

A

A premalignant condition:

Monoclonal Gammopathy of Uncertain Significance (MGUS)

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6
Q

Summarise the epidemiology of MGUS.

A

Incidence increases with age

Up to 1% - 3.5% in elderly

Average risk for progression: 1% annually​ (most don’t)

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7
Q

In MGUS, which Ig antibodies predispose for myeloma?

A

IgG

IgA

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8
Q

What does IgM MGUS progress to?

A

Lymphoma

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9
Q

What is MGUS associated with?

A

Osteoporosis

Thrombosis

Bacterial infection

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10
Q

What is the WHO diagnostic criteria for MGUS?

A

Serum M-protein <30g/L

BM clonal plasma cells <10%

No lytic bone lesions

No myeloma-related organ or tissue impairment

No evidence of other B-cell proliferative disorder

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11
Q

What are risk factors for MGUS?

A

Non-IgG M-spike

M-spike >15g/L

Abnormal serum free light chain (FLC) ratio

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12
Q

Which 2 criteria define smouldering multiple myeloma?

A

Serum monoclonal protein (IgG or IgA) >30g/L or urinary monoclonal protein >500mg per 24h +/- clonal BM plasma cells 10-60%.

Absence of myeloma defining events or amyloidosis.

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13
Q

What are risk factors for smouldering multiple myeloma?

A

BM myeloma cells ≥20%

M-spike ≥20g/L

Serum FLC ratio ≥20

>2 RFs = high risk

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14
Q

What is the general course for multiple myelome and related plasma cell disorders?

A
  1. MGUS
  2. Smouldering myeloma
  3. Symptomatic myeloma
  4. Remitting-relapsing
  5. Refractory
  6. Plasma cell leukaemia
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15
Q

How does multiple myeloma affect the bone marrow microenvironment?

A

Bone destruction

Anaemia

Angiogenesis

Immunosuppressants + infections

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16
Q

How is multiple myeloma diagnosed?

A

≥10% plasma cells in BM

or

Plasmacytoma + ≥1 CRAB or MDE

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17
Q

What is CRAB?

A

C: Hypercalcaemia: Calcium >2.75mmol/L

R: Renal disease: Creatinine >177μmol/L or eGFR <40ml/min

A: Anaemia: Hb <100g/L or drop by 20g/L

B: Bone disease: >,1 bone lytic lesion on imaging

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18
Q

What is MDE?

A

Myeloma Defining Events (MDE)

BM plasma cell pop. high ≥60%

Involved: Uninvolved FLC ratio >100

> 1 focal lesion in MRI (>5mm)

19
Q

What is the association between myeloma and bone disease?

A

80% myeloma patients present with bone disease

20
Q

6 features of clinical presentation in multiple myeloma patients?

A

Proximal skeleton

Back (spine), chest wall + pelvic pain

Osteolytic lesions, never osteoblastic

Osteopenia

Pathological fractures

Hypercalcaemia

21
Q

What are emergencies associated with bone disease in multiple myeloma patients?

A

Cord compression:

Dx + Tx within 24h

MRI scan

Ig + FLC studies +/- biopsy

Dexamethasone

Radiotherapy

Neurosurgery: rarely required

Stabilise unstable spine

MDT meeting

Hypercalcaemia:

Presents with drowsiness, constipation, fatigue, muscle weakness, AKI

Fluids, steroids, zolendronic acid

22
Q

Define myeloma kidney disease.

A

Serum creatinine >177μmol/L (>2mg/dL ) or eGFR <40ml/min (CDK-EPI)

AKI resulting from myeloma.

23
Q

What are causes of myeloma kidney disease?

A

Cast nephropathy is caused by high SFLC levels + Bence Jone proteinuria.

Hypercalcaemia, loop diuretics, infection, dehydration, nephrotoxics.

20-50% AKI at dx.

2-4% of newly diagnosed require dialysis.

24
Q

What is the association with myeloma kidney disease and prognosis of multiple myeloma?

A

12% early death

Prolonged hospital stay + lethal infections

25
Q

Why is multiple myeloma associated with immunodeficiency?

A

Immunoparesis: Low serum normal Igs

Myeloid, T cells + NK cells impairment

Chemotherapy impairs immune response

Myeloma immune evasion

26
Q

What is the diagnostic workup for multiple myeloma?

A

Immunoglobulin studies:

Serum protein electrophoresis

Serum FLC levels

24h Bence Jones protein

BM aspirate + biopsy: IHC for CD138

FISH analysis: Should include at least high risk abnormalities

Flow cytometry immunophenotyping

27
Q

What are common target organs of AL amyloidosis?

A

Kidney

Heart

Liver

Neuropathy

28
Q

What are 5 signs and symptoms of AL amyloidosis?

A

Nephrotic syndrome 70%: Proteinuria (not BJP!), peripheral oedema

Unexplained HF → determinant of prognosis: Raised NT-proBNP, Abnormal echocardiography + cardiac MRI

Sensory neuropathy

Abnormal LFTs

Macroglossia

29
Q

What is Monoclonal Gammopathy of Renal Significance (MGRS)?

A

Applies specifically to any B-cell clonal lymphoproliferation where there are:

  1. >,1 kidney lesions caused by mechanisms related to the produced monoclonal immunoglobulin (Ig).
  2. The underlying B cell clone does not cause tumor complications or meet current hematological criteria for immediate specific therapy.
30
Q

What is the pathophysiology of MGRS?

A

Rare disease, several subtypes

Demonstration of the involved monoclonal Ig or light chain possible in most cases

Work up similar to myeloma

Many require myeloma-type tx aiming to improve renal survival

Many lose kidney function

31
Q

Which drugs have been used for a long time in myeloma therapy?

A

Cytostatic drugs: Melphalan, Cyclophosphamide

Immunomodulatory drugs: Thalidomide, Lenalidomide

Steroids: Dexamethasone + Prednisolone

32
Q

Why are proteasome inhibitors useful in multiple myeloma?

A

Myeloma cells are protein production factories- all proteins made folded in ER.

Proteasome degrades misfolded protein

Causes accumulation of misfolded protein, ER stress + apoptosis

ER associated degradation (ERAD)

33
Q

What are some proteasome inhibitors used in the treatment of myeloma?

A

Bortezomib

Approved for first line or relapse

IV or S/C

Neuropathy is main toxicity

Carfilzomib

More potent than Bortezomib

Approved in relapse

IV only

Thrombocytopenia, cardiotoxicity

Ixazomib

Approved in relapse, in combination

Oral

Favourable toxicity profile

34
Q

Describe the pathogenesis of multiple myeloma

A

Primary event: Hyperdiploidy (60%) / IgH rearrangements

Secondary event: KRAS, NRAS, MYC

35
Q

Which is the most common cytogenetic abnormality in myeloma?

A

Hyperdiploid karyotype

36
Q

How does AL amyloidosis arise?

A

MGUS or myeloma in background

Misfolded SFLCs aggregate into amyloid fibrils in target organs

Amyloidogenic potential of FLC more important than amount

37
Q

How may Amyloid fibrils be recognised?

A

Stain with Congo Red

Solid, non-branching + randomly arranged

38
Q

Name a key histopathological myeloma marker

A

CD138

39
Q

Name 2 anti-CD38 moAbs and state their MOA

A

Daratumumab

Isatuximab

Binds CD38 on MM cells

Initiates complement cascade → cell death

Binds CTL + Macrohages → cell death

Crosslinking → Apoptosis

40
Q

What type of response has the best prognosis, and thus is what treatment aims for?

A

Complete response, minimal residual disease negative (MDR -ve)

Complete response alone is not enough, as MDR +ve patients have worse outcome

41
Q

Name 3 emerging therapeutic agents entering myeloma standard of care

A

CAR T-cell therapy

BiTE

Immunoconjugates: brings together tumour cell + effector T cell, stimulates T cell to kill tumour cell

42
Q

Why are steroids used in multiple myeloma?

A

Induce apoptosis in myeloma cells

Strong synergy, part of almost all combination regimens

43
Q

Describe the use of Melphalan in multiple myeloma

A

Autologous Haematopoietic Stem Cell Transplant

  1. Stem cells harvested from blood + stored
  2. High dose Melphalan used to kill myeloma cells (alkylating agent→X-links)
  3. Re-infusion of stem cells to rescue blood formation
44
Q

Describe the use of Thalidomide in multiple myeloma

A

Targets the turnover of transcription factors that are key to myeloma cell survival

YR5 Haematology (20 decks)

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